Recently, Weinberger and McClure1 offered a provocative and cautionary perspective in connection with mounting longitudinal neuroimaging evidence of progressive brain volume decline in schizophrenia. Unfortunately, they confuse this increasingly well-documented phenomenon with a neurodegenerative hypothesis of schizophrenia. We agree with the authors that neurodegenerative processes involving inflammation and neuronal loss are unlikely based on the neuropathology literature, and that volumetric magnetic resonance imaging (MRI) data cannot elucidate the cellular or molecular mechanisms underlying progressive volume loss. This does not diminish the importance of longitudinal neuroimaging studies, whose rationale is to examine whether brain dysmorphology is static or progressive. This rationale is as valid today as it was in 19882 and 1994,3 when Dr Weinberger's group reported nonprogressive ventricular enlargement in schizophrenia and cited these findings as evidence that schizophrenia is a static neurodevelopmental encephalopathy.4 In contrast with these early studies, most of which used computed tomography, recent positive studies are generally based on quantitative volumetric MRI methods, including gray-white segmentation, and larger sample sizes, including carefully chosen control groups, and may therefore warrant greater weight. Moreover, progressive brain changes do not preclude a neurodevelopmental insult in schizophrenia, since an inherited neurodevelopmental abnormality can also exhibit progressive features. Examples include Huntington disease, Down syndrome, and probably autism, to name a few.
Mathalon DH, Rapoport JL, Davis KL, Krystal JH. Neurotoxicity, Neuroplasticity, and Magnetic Resonance Imaging Morphometry. Arch Gen Psychiatry. 2003;60(8):846-848. doi:10.1001/archpsyc.60.8.846